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Origins of cell diversity in multicellular tissues

Project description

Role of stochastic processes in the origin of cell phenotypic diversity in multicellular tissues

Molecular mechanisms that coordinate the simultaneous emergence of multiple cell types from a homogeneous population on a tissue-wide scale are less studied than the molecular signals that specify an individual cell’s fate. Increasing evidence suggests that stochastic processes are critical for the emergence of cell diversity in multicellular tissues. Funded by the Marie Skłodowska-Curie Actions programme, the ORGANIZE project aims to test the hypothesis that different combinations of dynamic molecular signals at the single-cell level drive cell population patterning at the tissue level, creating phenotypic diversity. Using mouse intestinal organoids as a model multicellular system, the project will employ single-cell imaging, transcriptomics and optogenetic control of tissue heterogeneity to identify the molecular drivers of phenotypic diversity.

Objective

Multicellular tissues, and ultimately complex organisms, are composed of multiple distinct cell types that differ in functional attributes. Such diversity in cell composition (i.e. phenotypic diversity) arises during development and regeneration, where progenitor cells differentiate along multiple cell fate lineages to form a heterogeneous population. While the molecular signals (i.e. cell states) that specify individual cell fates are widely studied, less is known about how multiple cell types can simultaneously emerge from a seemingly homogeneous population and which molecular mechanisms coordinate this process on a tissue-wide scale. Increasing evidence suggests that stochastic events, as opposed to hard-wired deterministic processes, are critical for emergence of heterogeneity. However, the molecular mechanisms that drive stochasticity and diversity in a mammalian tissue remain unknown, mainly due to a scarcity of tools to measure stochastic events in large numbers of single cells and to perturb cell-to-cell heterogeneity on a tissue level. Here I propose to use quantitative single-cell imaging, transcriptomic approaches, and optogenetic control of tissue heterogeneity to identify the molecular mechanisms driving phenotypic diversity. I will apply these techniques to mouse intestinal organoids, a multicellular system that recapitulates the intestinal epithelium. I hypothesize that variability in cell state (at the single-cell level) drives cell phenotypic diversity (at the tissue level). Different combinations of dynamic molecular signals within single cells may thereby pattern populations within a tissue to adopt specific fate outcomes. Gaining insight into the mechanisms of phenotypic diversity will answer fundamental questions in developmental and synthetic biology on the origins of cell diversity in multicellular tissues, how stochastic processes can ensure developmental robustness, and the maintenance of phenotypic equilibrium in homeostasis and disease.

Coordinator

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Net EU contribution
€ 191 149,44
Address
MAULBEERSTRASSE 66
4058 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Research Organisations
Links
Total cost
€ 191 149,44